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Synthetic Cannabinoids

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Part of OutCo's science talks, this presentation is focused the history and bioactivity of synthetic cannabinoids.

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Synthetic Cannabinoids

  1. 1. www.outco.com Synthetic Cannabinoids Dr. Markus Roggen 1
  2. 2. www.outco.com 1.Same but different 2.The opioid epidemic 3.The dawn of synthetic cannabinoids 4.The Good 5.The Bad 6.The Ugly 7.The Future 2 Abstract
  3. 3. www.outco.com 3 Same but different How small changes in molecular structure have huge effects
  4. 4. www.outco.com Molecular structure has a huge effect on how molecules interact with the human body. Small changes in stereochemistry, functional groups or carbon backbone will change the effect. 4 Same but Different
  5. 5. www.outco.com Vanilla • Second most expensive spice • Worlds favored flavoring • 95% of all “vanilla” products use synthetic vanillin • Real vanilla better for cookies, syn. vanillin for baking 5 Same but Different Real Fake Plus hundreds of other compounds
  6. 6. www.outco.com Total Synthesis vs. Semisynthesis • Taxol is an anticancer drug isolated from Pacific Yew • First total synthesis by Holton: 46 linear steps • Semisynthesis by Holton with 80% yield from European Yew 6 Same but Different
  7. 7. www.outco.com 7 The Opioid Epidemic A Case Study
  8. 8. www.outco.com • Heroin acts on opioid receptor • Relieves pain • Produces feeling of euphoria • Highly addictive • High doses can depress breathing • Naxloxone reverses effects of opioid overdose • Has stronger affinity for opioid receptor • Works within 2 minutes of injection 8 The Opioid Epidemic
  9. 9. www.outco.com • Fentanyl is a synthetic opioid, prescribed by doctors for chronic pain • Higher potency increases risk of overdose 9 The Opioid Epidemic
  10. 10. www.outco.com 10 Synthetic Cannabinoids Shout out to Clemson
  11. 11. www.outco.com • Professor Emeritus, Organic Chemistry, Clemson University • Began in 1984 to synthesis novel cannabinoids • Focused on targeting endocannabinoid receptors • For multiple sclerosis, HIV, chemoterapy, … • Over 450 synthetic cannabinoids developed • First used as marijuana alternatives in Germany in late 2000s 11 John William Hoffman
  12. 12. www.outco.com • Professor, Department of Medicinal Chemistry, Northeastern University • Study of interactions ‘cannabinoid-like’ molecules with CB1 & CB2 receptor • Design and synthesis of novel therapeutically useful drugs for pain, appetite and central nervous system diseases 12 Alexandros Makriyannis
  13. 13. www.outco.com • Professor, Department of Medicinal Chemistry, Hebrew University of Jerusalem • First to isolate, characterize and synthesis of THC • Isolated and identified endocannabinoids • HU-210 • Promotes proliferation, but not differentiation, of hippocampal neural stem and progenitor cells • Indication of antianxiety and antidepressant effects • Implicated in inflammation prevention due to amyloid beta proteins involved in Alzheimer’s 13 Raphael Mechoulam
  14. 14. www.outco.com • Synthesized in the 1970s and 1980s • Recently discovered in recreational drugs • CP 55,940 • Widely used cannabinoid research tool • Neuroprotective by reducing intracellular calcium release 14 Pfizer
  15. 15. www.outco.com • Molecules that target CB1 & CB2 receptors • No precedent in scientific literature • Appear to be rationally designed • Little to no information about pharmacology and toxicology 15 Designer Cannabinoids
  16. 16. www.outco.com • Agonist binds to receptor: Key for the lock • Full: Copy of key • Partial: Lock Pick • Inverse: Opposite effect of normal • Antagonist blocks others from binding: Putty for lock 16 Terms and Conditions
  17. 17. www.outco.com • THC: Partial agonist to CB1 & CB2 • CBD: Antagonist for CB1 & CB2 • 2-AG: Full agonist for CB1 17 Terms and Conditions
  18. 18. www.outco.com • All claims made are ’soft’ • Didn’t find a drug that is FDA approved • Most studies are in animal models or in vitro • Therefore not directly applicable to humans 18 Terms and Conditions
  19. 19. www.outco.com 19 The Good Cannabinoid Analogs in Medical Research
  20. 20. www.outco.com • Full CB agonist • Potent analgesic (painkiller) • Prevent inflammation caused by amyloid beta proteins involved in Alzheimer’s disease • Prevent cognitive impairment, loss of neuronal markers • Reduces voluntary wheel running in mice 20 WIN 55,212-2
  21. 21. www.outco.com • Potent CB2 agonist • 200x more selective for CB2 over CB1 • Not psychoactive as CB2 selective • Prevent inflammation caused by amyloid beta proteins involved in Alzheimer’s disease 21 JWH-133
  22. 22. www.outco.com • Prof. Bob Moore II, University of Tenesee • CB2 inverse agonist • In pre-clinical development for treatment of neurodegenerative disorders and traumatic brain injury 22 SMM-189 doi: 10.1002/prp2.159
  23. 23. www.outco.com 23 The Bad Bath Salts and others
  24. 24. www.outco.com • Anti-obesity drug / appetite suppressant • Inverse agonist for CB1 • Approved in 2006 (EU), first of its class • Withdrawn in 2008 • Risk of serious psychiatric problems • 10% experience depressive disorders • 1% suicidal ideation • Additionally: nausea, upper respiratory tract infections, anxiety, insomnia, diarrhea, vomiting, … 24 Rimonabant, Sanofi-Aventis
  25. 25. www.outco.com • Full agonist for CB1 & CB2 • Similar effects to THC, but 5x greater • Death linked to JWH-018 by drug toxicity and organ failure 25 JWH-018
  26. 26. www.outco.com 26 The Ugly “The is some weird shit, man”
  27. 27. www.outco.com • “Unnatural” enantionmer of HU-210 • Not a CB agonist • NMDA antagonist • Anesthetic effect like ketamine or synthetic opioids • No cannabis-like effects • But anticonvulsant and neuroprotective • Studied for treating head injury, stroke, or cancer • Currently in Phase I for treating brain cancer 27 Dexanabinol
  28. 28. www.outco.com • Patented by Mark Scialdone, PhD • He reports similar ‘High’ as THC • No further clinical study beyond his own consumption • He hydrogenated cannabis extract, then consumed it 28 Hydrogenated Cannabinoids
  29. 29. www.outco.com 29 The Future What is there to come?
  30. 30. www.outco.com • Protecting Groups can be used to prevent metabolizing of compound 30 Protecting Groups
  31. 31. www.outco.com • Most interesting sites for modification • C-11 methyl group • C5 side chain 31 Active Sites
  32. 32. www.outco.com • Different cannabinoid inspired structures as starting point for active compound 32 Different Cannabinoid Scaffold

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